Efficient Synthesis of 4H-3,1-Benzoxazine Derivatives via One-Pot Sequential Passerini-Azide/Palladium-Catalyzed Azide–Isocyanide Coupling/Cyclization Reaction

Abstract

A new, one-pot method for the synthesis of 4H-3,1-benzoxazine derivatives has been developed. The Passerini-azide reactions of 2-azidobenzaldehydes, trimethylsilyl azide, and isocyanides produced azide intermediate without separation, which then reacted with isocyanides to give 4H-3,1-benzoxazine derivatives via a tandem one-pot palladium-catalyzed azide–isocyanide coupling/cyclization reaction in moderate to good yields.

Key words

4H-3,1-benzoxazine derivatives - one pot - Passerini-azide reaction - palladium - azide–isocyanide coupling

• References and Notes

• 1 These authors contributed equally.
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• 23 General procedure for the one-pot preparation of 4H-3,1-benzoxazines 5: A mixture of 2-azidobenzaldehyde 1 (2 mmol), trimethylsilyl azide (2 mmol), and isocyanide 2 (2 mmol) was stirred in CH₂Cl₂ (10 mL) at room temperature for 3 days. After the solvent was removed under reduced pressure, THF (5 mL) was added, then isocyanide 4 (3 mmol) and Pd(PPh₃)₄ (0.2 mmol) were added sequentially to the reaction system, and the solution was stirred at 60 °C for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (EtOAc/petroleum ether, 1:10) to afford product 5. 5a: Yield: 0.552 g (84%); yellow solid; mp 145–146 °C; ¹H NMR (CDCl₃, 600 MHz): δ = 7.26 (t, J = 8.4 Hz, 1 H), 7.07 (d, J = 7.8 Hz, 1 H), 6.89 (t, J = 7.2 Hz, 2 H), 6.46 (d, J = 7.8 Hz, 1 H), 4.40 (s, 1 H), 1.68 (s, 9 H), 1.40 (s, 9 H). ¹³C NMR (CDCl₃, 150 MHz): δ = 151.9, 150.3, 141.8, 130.0, 123.6, 123.0, 122.7, 119.8, 70.0, 62.6, 51.5, 30.4, 29.2. LCMS (ESI): m/z [M + H]⁺ = 329. Anal. Calcd for C₁₇H₂₄N₆O: C, 62.17; H, 7.37; N, 25.59. Found: C, 62.49; H, 7.81; N, 25.72.